DESCRIPTION: (Applicant's abstract) There is a great need for a safe drug therapy for stroke that does not involve transmitter receptor blockade or haemorrhagic risk. Ampakines are a novel group of allosteric positive modulators that target AMPA-type glutamate receptors. Ampakines improve learning and memory retention in rats and humans, and new data indicate that they also improve repair potential following stroke-like excitotoxicity, perhaps by augmenting signaling events underlying cellular protection cascades. The objective of the propose Phase I experiments is to determine if Ampakines have the potential to be commercially valuable for preventing and/or reducing the degeneration associated with stroke-related impairments. This work will take advantage of a model system consisting of cultured slices of hippocampus, a brain region particularly vulnerable to ischemia. Project One will test whether Ampakines attenuate the hallmark effects of an excitotic episode in slice cultures; these include production of cytoskeletal breakdown products and the loss of synaptic proteins. Project Two will then determine whether Ampakines enhance the recovery and long-term survival of neurons. The results of these studies should provide insight into the utilization of glutamatergic modulatory ligands as neuroprotectants. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE